Dialkylaminoalkyl phenoxyphenylalkanoates



United States Patent Ofifice 3,064,037 DIALKYLAMINOALKYL PHENOXYPHENYL- ALKANOATES James F. Kerwin, Broomall, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Sept. 28, 1961, Ser. No. 141,313 8 Claims. (Cl. 260473) This invention relates to novel organic compounds having useful biological properties and more specifically to amino and dialkylaminoalkyl esters of substituted phenoxyphenyl alkanoic acids. In addition to these valuable hypocholesterolemic compounds themselves, this invention also pertains to processes for their preparation.

The compounds embraced herein may be represented by the following structural formula:

/lower alkyl 30- 40112) n-ooo- (CH1) ,-N

I l lower alkyl R I I wherein Each of R and R is hydrogen, iodo, or lower alkyl, B is hydrogen or lower alkyl,

11 is a positive integer from 0 to 3,

x is a positive integer from 2 to 3.

By the term lower alkyl is intended a straight or branched chain hydrocarbon of from one to six carbon atoms, as for example methyl, ethyl, isopropyl, t-butyl and the like.

This invention also includes within its scope the pharmaceutically acceptable non-toxic salts of the above defined bases which are formed from non-toxic organic and inorganic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or by treatment of the base with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, the desired salt thereby separating directly. Exemplary of such pharmaceutically acceptable non-toxic organic salts are those formed with acids such as maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, 'citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic, as well as with the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.

The compounds of this invention possess the ability to normalize high lipid levels in the serum and tissue. At the same time however, the calorigenic properties of these compounds are surprisingly low, thereby minimizing cardiac manifestations such as angina which are so prevalent in many of the antihypercholesterolemic agents of this type. This Very favorable cholesterol loweringcalorigenic ratio renders these compounds as valuable therapeutic agents for the safe reduction of abnormally high cholesterol levels in the animal organism.

The administration of these compounds may be made by any of the usual methods although the preferred route is oral. For actual administration, the usual pharmaceutical compositions such as tablets, capsules, sus pensions and the like may be employed. Also highly useful forms are sustained time release compositions 3,fi4,037 Patented Nov. 13, 1962 which provide a substantially uniform dosage over an extended period of time.

The compounds of this invention may be prepared by treating a compound of the formula:

R Ii II in which R, R, B and n are as above defined with an aminochloroalkane of the formula:

lower alkyl Cl-(OHgh-N lower alkyl wherein x is as above defined.

Generally these reagents represented by II and III are refluxed in an organic solvent such as ethanol, isopropanol, dioxane or the like, the product separating directly upon cooling of the reaction mixtures. This product is in the form of the hydrochloride salt and is converted to the free amine by treatment with aqueous alkali. The free amines so obtained may then be converted to other pharmaceutically acceptable non-toxic salts as herein described.

The preferred compounds of the present invention are those wherein R is iodo, B and R are hydrogen, n is 3 and x is 2.

The following examples will further serve to typify this invention but these examples are not to be construed as limiting the scope of this invention, the scope being defined by the appended claims.

' EXAMPLE 1 A mixture of 3.1 g. of 4-(3-iodo-4-hydroxyphenoxy)- III . 3,5-diiodophenylacetic acid and 0.8 g. of Z-diethylaminochloroethane is refluxed for 4 hours in ml. of anhydrous isopropanol. At the end of this time the solution is cooled and the solid which forms is collected by filtration and recrystallized from ethanol-petroleum ether to yield the diethylaminoethyl ester of 4-(3-iodo-4- hydroxyphenoxy)-3,5-diiodophenylacetic acid as the hydrochloride.

In a similar fashion 4-(4-hydroxyphenoxy)-3,5-diiodophenylacetic acid is employed in the procedure of this example and there is thus obtained the compound diethylaminoethyl 4 (4 hydroxyphenoxy)-3,5-diiodophenyl acetate as the hydrochloride.

EXAMPLE 2 The following compounds are substituted for the substituted acetic acid in Example 1: 4-( 3-iodo-hydroxy-pl1enoxy)-3,5-diiodobenzoic acid, 4-(4-hydroxyphenoxy) -3,5- diiodobenzoic acid, 4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodophenylbutyric acid and 4-(4-hydroxyphenoxy)-3,5-diiodophenylbutyric acid. There are thus obtained from this procedure the corresponding diethylaminoethyl esters as their hydrochlorides: diethylaminoethyl 4-(3-iodo-4- hydroxyphenoxy)-3,S-diiodobenzoate, diethylaminoethyl 4- (4-hydroxyphenoxy) 3,5 -diiodobenzoate, diethylam-inoethyl 4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodopheny1butyrate and diethylaminoethyl 4-(4-hydroxyphenoxy)-3,5- diiodophenylbutyrate.

EXAMPLE 4 The following compounds are employed as starting materials in place of 4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodophenylacetic acid (Reagent A) and Z-diethylaminochloroethane (Reagent B) in the procedure of Example 1.

Reagent A (a) 4-(3,5-diiodo-4-hydroxyphenoxy) -3,5-diiodophenylpropionic acid.

(b) 4-(4-methoxyphenoxy)-3,5-diiodobenzoic acid.

() 4-(4-methoxyphenoxy-3,S-diiodophenylpropionic acid.

(d) 4-(3,5-di-t-butyl-4-hydroxyphenoxy)-3,5-diiodophenylpropionic acid.

Reagent B (a) 1-dimethylamine-S-chloropfopane. (b) 1-diethylan1ine-3-chloropropane. (c) 1-diethylamine-3-chloropropane. (d) 1-dibutylamine-Z-chloroethane.

There are thus formed the following compounds as their hydrochloride:

(a) 3-dimethylaminopropyl 4-(3,5-diiodo 4-hydroxyphenoxy)-3,5-diiodophenyl propionate (b) 3-diethylaminopropyl 4-(4-methoxyphenoxy) -3,5-

diiodo benzoate (c) 3-diethylaminopropyl 4-(4-methoxyphenoxy)-3,5- diiodophenyl propionate (d) Z-dibutylaminoethyl 4-(3,5-di-t-butyl-4-hydroxyphenoxy)-3,5-diiodophenyl propionate EXAMPLE 5 The compounds obtained in the above examples are in the form of the hydrochloride salt and are transformed into their free acid and thence to their pharmaceutically acceptable acid addition salts according to the usual methods known to the art of the following being representative.

One gram of diethylaminoethyl 4-(3-iodo-4-hydroxyphenoxy)-3,5-diiodophenyl acetate hydrochloride is dissolved in Water and the solution rendered alkaline by the addition of aqueous sodium bicarbonate. The oil which forms is collected, dried over anhydrous magnesium sulfate, and dissolved in anhydrous acetone. There is then added 1 g. of maleic acid and the mixture stirred for 30 minutes. The solid which forms is collected by filtration and dried to yield diethylaminoethyl 4-(3-iodo-4hydroxyphenoxy)-3,5-diiodophenyl acetate as the maleate salt.

EXAMPLE 6 The following procedure is representative of the method methoxide.

4 with 3.12. g. of silver sulfate and at the end of this time the resultant silver bromide is removed by filtration. The filtrate is evaporated under reduced pressure to yield di- 2-isopropylmethoxyphenyl) -iodinium sulfate.

To 50 ml. of dry methanol is added 4.3 g. of ethyl 3,5- diiodo-4-hydroxyphenyl acetate, 4.8 g. of di-(2risopropylmethoxyphenyl)-iodonium sulfate and 0.7 g. of sodium The mixture is refluxed for 1 /2 hours and at the end of this time steamed distilled. The residue is then extracted with warm benzene and these extracts washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual oil is refluxed for 2 hours with 27 ml. of acetic acid and 85 for preparing the requisite starting materials of this in- V vention.

' Di (2 isopropylmethoxyphenyl) iodonium bromide (10.1 g.) (prepared from Z-isopropylmethoxybenzene according to the procedure described in US. Patent No. 2,839,583) is moistened with ethanol and suspended in 50 ml. of water. The suspension is shaken for 1%. hours ml. of consant-boiling hydriodic acid. The mixture is then filtered through diatomaceous earth and evaporated to dryness under reduced pressure. The material is taken up in hot ethanol and the solid which forms upon cooling and addition of benzene is collected by filtration and dried to yield 4-(3-isopropyl-4-hydroxyphenoxy)-3,5'diiodophenylacetic acid.

This compound is then refluxed with diethylaminoethyl chloride in dry isopropanol according to the procedure of Example 1. There is thus obtained the diethylaminoethyl ester of 4-(3-isopropyl-4-hydroxyphenoxy)-3,5-diiodophenylacetic acid as the hydrochloride.

I claim:

1. A compound selected from the group consisting of amines of the structural formula:

lower alkyl wherein:

i R and R are each a member selected from the group consisting of hydrogen, iodo, and lower alkyl; B is a member selected from the group consisting of hydrogen and lower alkyl; n is a positive integer from 0 to 3 inclusively; x is a positive integer from 2 to 3 inclusively and the pharmaceutically acceptable non-toxic acid addition salts thereof.

2. A compound according to claim 1 wherein R is iodo, R is hydrogen and B is lower alkyl. 3. A compound according to claim 1 wherein R is iodo, R is lower alkyl and B is lower alkyl.

4. A compound according to claim 1 wherein R is lower alkyl and R and B are hydrogen.

5. The diethylaminoethanol ester of 4-(4-hydroxy3- iodophenxoy}-3,5-diiodophenylacetic acid.

6. The diethylaminoethanol ester of 4-(4-hydroxy-3- isopropylphenoxy) -3,5-diiodophenylacetic acid.

7. The hydrochloride acid-addition salt of the base defined by claim 5.

8. The hydrochloride acid-addition salt of the base defined by claim 6.

References Cited in the file of this patent UNITED STATES PATENTS 2,844,621 Bernstein of al. July 22, 1958 2,928,845 Shapiro et al. Mar. 15, 1960 2,970,165 Michel et a1. Jan. 31, 1961 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AMINES OF THE STRUCTURAL FORMULA: 